Methylation of lysine residues within the N-terminal portion of histones plays an important role in regulation of gene transcription. Recently, we identified an essential role of histone methyltransferase G9a, which dimethylates lysine 9 of the histone H3 (H3K9), in regulation of antiviral responses in vitro. We found that G9a deficiency leads to selective up-regulation of basal and virus-induced expression of genes controlling type I interferon (IFN) gene expression and expression of IFN-inducible genes. Up-regulation of antiviral gene expression was associated with the robust resistance of G9a-deficient fibroblasts to several RNA viruses. [unreadable] [unreadable] We hypothesize that G9a is responsible for the epigenetic control of antiviral gene expression. We argue that in the absence of viral infection, the expression of the IFN and IFNa/[unreadable]-inducible genes is silenced by G9a. Conversely, we suggest that efficient response to RNA viruses is associated with and depends upon reversal of G9a-mediated antiviral gene suppression. In the proposal, we will address the mechanism of G9a involvement in antiviral response. We will determine whether cell responses to RNA viruses or IFNa/[unreadable] are associated with changes in G9a function and histone methylation. [unreadable] [unreadable] Resistance of G9a-deficient cells to murine RNA viruses suggests G9a as a possible target for antiviral therapy. To study the relevance of G9a in antiviral therapy, we propose to evaluate the impact of G9a deficiency on mouse and human cell responses to influenza A and hepatitis C virus respectively. Overall, our studies will provide an insight into the mechanism and physiological significance of a novel chromatin-mediated pathway of antiviral cell response. [unreadable] [unreadable] [unreadable]